Cyclopropanone (I) is a very reactive reactive ketone. ##STR3## It is so reactive that it can only be detected at low temperatures in the strict absence of water and other hydroxylic substances. However, the enormous reactivity of cyclopropanone toward water, alcohols, thiols, amines, and other nucleophiles is a key to its potential utility. Stated in terms of chemical equilibria: the adducts of cyclopropanone with nucleophiles are very strongly favored over uncomplexed cyclopropanone. Equations 1-4 provide examples of such favored adducts. ##STR4## J. S. Wiseman and R. H. Abeles have reported in the article "The Mechanism of Inhibition of Aldehyde Dehydrogenase by Cyclopropanone Hydrate and the Mushroom Toxin Coprine", Biochemistry 18 (1979) 427-435, the potential of cyclopropanone as an enzyme inhibitor and of coprine (II), a naturally-occurring adduct of cyclopropanone with the amide group of glutamine. ##STR5## Coprine is a potent inhibitor of the enzyme, alcohol dehydrogenase.
Wiseman and Abeles hypothesized that the inhibition results from the release of cyclopropanone, which reacts with a sulfhydryl group at the active site of the enzyme, thereby inhibiting the enzyme. ##STR6## They then report demonstrating experimentally the inhibitory power of cyclopropanone with alcohol dehydrogenase and with other enzymes.
If cyclopropanone could be systematically controlled and synthesized, it could provide a mechanism for converting many enzyme substrates into potent and highly specific inhibitors. The list of substrates could include steriods, peptides, alkaloids, prostaglandins, and other physiologically active substances.
Assuming the proper cyclopropanone derivative could be prepared and attached to a substrate, one would have a new substance with the inhibitory potential of cyclopropanone and, in favorable instances, with the specificity associated with the natural substrate. However, a problem now exists in that synthesis in the cyclopropane area is in a very rudimentary state even though the prior art discloses a variety of cyclopropanone derivatives and processes for their production, e.g., U.S. Pat. No. Re. 27,592; U.S. Pat. No. 2,815,362; U.S. Pat. No. 2,967,181; U.S. Pat. No. 3,047,611; U.S. Pat. No. 3,156,722; U.S. Pat. No. 3,184,509; U.S. Pat. No. 3,341,66; U.S. Pat. No. 3,335,481; U.S. Pat. No. 3,462,491; U.S. Pat. No. 3,711,547; U.S. Pat. No. 3,711,548; U.S. Pat. No. 3,728,388; U.S. Pat. No. 4,076,840; U.S. Pat. No. 4,264,527; and Russian Pat. No. 524,788. O. Pelletier and K. Jankowski, Can. J. Chem., 60, 2383 (1982), disclose the synthesis of a cyclopropanone ketal ester from a copper sulfate catalyzed reaction of ethyl diazoacetate with 1,1-diethoxyprop-1-ene. The reported properties of the synthesized ester are suspect and could not be verified.
Among the most desirable molecules for attachment to enzyme substrates are the protected cyclopropanones identified below as structures III, IV, and V. A synthetic approach to this series might make use of the readily available ethyl diazoacetate (VI) ##STR7## and diethyl ketene acetal (VII) to prepare the precursor ester (VIII). ##STR8## This conventional approach fails to yield the desired precursor ester VIII and instead yields an open product IX which is reported by M. F. Dull and P. G. Abend in "The Reaction of Some Methylene Derivatives with Ketane Diethylacetal", J. Am. Chem. Soc. 81 (1959), 2588. The reason for the failure is not known. Possibly the reaction between compound VI and compound VII might yield compound VIII, but compound VIII is unstable and decomposes to compoud IX by a hydrogen transfer reaction, as shown below. ##STR9##
It might be possible to circumvent the rearrangement of configuration VIII to IX by controlling the architecture of the product. Using this concept, it has now surprisingly and unexpectedly been found that the cyclopropanone ketal esters, and other derivatives of cyclopropanone can be successfully synthesized. Such derivatives can be used as chemical intermediates and demonstrate different degrees of effectiveness as biological inhibitors.